Cyclic Thiol Prodrugs

Abstract

Disclosed herein are cyclic thiol prodrugs, and pharmaceutical compositions thereof. The prodrugs and pharmaceutical compositions thereof may be used to treat or prevent medical disorders such as, for example, cystinuria, cystinosis, cancer, neurodegenerative disease, Parkinson's disease, Huntington's disease, malaria, nonalcoholic fatty liver disease, radiation poisoning, arsenic poisoning, radioprotection, Wilson's disease or rheumatoid arthritis.

What is claimed is: 
     
         1 . A compound of structural Formula (I): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts, hydrates or solvate thereof wherein: 
         D is —NR 7 R 8 ; 
         A is —CHR 9 , —CHR 10 CHR 11 , —CHR 12 CHR 13 CHR 14 ; 
         B is —S—, —NR 15  or —CH 2 NR 31 ; 
         Z is —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, —CO 2 R 16 , —CO 2 NR 17 R 18 , —CH 2 OR 19  or —CN; 
         R 7  and R 8  are independently —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl or R 7  and R 8  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl heterocycloalkyl, substituted heterocycloalkyl, heterocycloalkenyl or substituted heterocycloalkenyl ring; 
         R 15  is —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl; 
         R 16 , R 19 , R 20 , R 23 , R 24 , R 27 , R 28  and R 31  are independently —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl or substituted heteroarylalkyl; 
         R 9  is —H, alkyl, alkenyl, aryl, —CO 2 R 20 , —CO 2 NR 21 R 22 , —CH 2 OR 23  or —CN; 
         R 10  and R 11  are independently —H, alkyl, alkenyl, —CO 2 R 24 , —CO 2 NR 25 R 26 , —CH 2 OR 27 , —CN or R 10  and R 11  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl ring; 
         R 12 , R 13  and R 14  are independently —H, alkyl, alkenyl, —CO 2 R 28 , —CO 2 NR 29 R 30 , —CH 2 OR 31 , —CN or R 12  and R 13  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl ring, or R 13  and R 14  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl ring or R 10  and R 12  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl ring; 
         R 17  and R 15  are independently —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl or substituted heteroarylalkyl or R 17  and R 18  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl ring; 
         R 21  and R 22  are independently —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkyl or R 21  and R 22  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl ring; 
         R 25  and R 26  are independently —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkyl or R 25  and R 26  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl ring; 
         R 29  and R 30  are independently —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkyl or R 27  and R 28  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl ring; and R 31  is —H or alkyl; provided that R 7  and R 8  are not both —H. 
       
     
     
         2 . The compound of  claim 1 , wherein R 7  and R 8  are independently —H, substituted alkyl, substituted alkenyl, substituted arylalkyl, substituted arylalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, substituted heteroarylalkyl, substituted heteroarylalkenyl. 
     
     
         3 . The compound of  claim 1 , wherein R 7  and R 8  are independently —H, substituted alkyl, substituted alkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl or substituted heteroalkenyl. 
     
     
         4 . The compound of  claim 1 , wherein R 7  and R 8  are independently —H, substituted alkyl or substituted alkenyl. 
     
     
         5 . The compound of  claim 1 , wherein R 7  and R 8  are independently —H, —CHR 32 CO 2 R 33 ; R 32  is —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl or substituted heteroaryl; and R 33  is alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl. 
     
     
         6 . The compound of  claim 1 , wherein R 7  and R 8  are independently —H, —CHR 32 CO 2 R 33 ; R 32  is —H, alkyl, substituted alkyl, alkenyl or substituted alkenyl; and R 33  is alkyl, alkenyl or arylalkenyl. 
     
     
         7 . The compound of  claim 6 , wherein R 7  and R 8  are independently —H, or 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 6 , wherein one of R 7  and R 8  are —H, and the other of R 2  and R 3  are 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , wherein R 15  is —H, alkyl, substituted alkyl, alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl; and R 16 , R 19 , R 20 , R 23 , R 24 , R 27 , R 28  and R 31  are independently —H, alkyl, substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, heteroalkenyl or heteroaryl; R 21  and R 22  are independently —H, alkyl, substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, heteroalkenyl, heteroaryl or R 21  and R 22  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl ring; R 25  and R 26  are independently —H, alkyl, substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, heteroalkenyl, heteroaryl or R 25  and R 26  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl ring; R 29  and R 30  are independently —H, alkyl, substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, heteroalkenyl, heteroaryl or R 27  and R 28  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl ring. 
     
     
         10 . The compound of  claim 9 , wherein B is —NR 15 . 
     
     
         11 . The compound of  claim 10 , wherein A is —CHR 9 . 
     
     
         12 . The compound of  claim 11 , wherein Z is —H, —CO 2 R 16  or —CO 2 NR 17 R 18 . 
     
     
         13 . The compound of  claim 12 , having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 11 , wherein A is —CHR 12 CHR 13 CHR 14 . 
     
     
         15 . The compound of  claim 14 , wherein Z is —H. 
     
     
         16 . The compound of  claim 15  having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 1 , wherein B is —S—. 
     
     
         18 . The compound of  claim 17 , wherein A is —CHR 9 . 
     
     
         19 . The compound of  claim 18 , wherein Z is —CO 2 R 16  or —CH 2 OR 19 . 
     
     
         20 . The compound of  claim 19  having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 1 , wherein B is —CH 2 NR 31 —. 
     
     
         22 . The compound of  claim 21 , wherein A is —CHR 9 . 
     
     
         23 . The compound of  claim 22 , wherein Z is H. 
     
     
         24 . The compound of  claim 23  having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         25 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable vehicle. 
     
     
         26 . A method of treating cystinosis, cancer neurodegenerative disease, Parkinson's disease, Huntington's disease, malaria, nonalcoholic fatty liver disease, radiation poisoning, arsenic poisoning, radioprotection, Wilson's disease or rheumatoid arthritis comprising administering to the patient in need thereof a therapeutically effective amount of a compound of  claim 1 .